Dysregulated lipid metabolism is commonly observed in septic patients, but how it contributes to sepsis remains largely unknown. Reverse cholesterol transport (RCT) is crucial for regulating cholesterol metabolism in circulation. During RCT, high-density lipoprotein (HDL) collects cholesterol from peripheral tissues and transports it to the liver's scavenger receptor BI (SR-BI), where SR-BI mediates the uptake of cholesteryl esters from HDL for excretion via bile. In this study, we utilized AlbCreSR-BIfl/fl mice, a model with impaired RCT, to investigate the impact of RCT on sepsis. We found that AlbCreSR-BIfl/fl mice were significantly more susceptible to cecal ligation and puncture (CLP)-induced polymicrobial sepsis, with a survival rate of 14.3% compared to 80% in SR-BIfl/fl littermates. Mechanistically, sepsis disrupted cholesterol metabolism, causing a 4.8-fold increase in free cholesterol (FC) levels and a 4-fold increase in the FC/cholesteryl ester (CE) ratio in AlbCreSR-BIfl/fl mice compared to SR-BIfl/fl littermates. This disruption led to hemolysis and death. Notably, administering the cholesterol-lowering drug probucol normalized FC levels and the FC/CE ratio, and significantly improved survival in CLP-AlbCreSR-BIfl/fl mice. However, probucol treatment reduced survival in CLP-LDLR-/- mice, which had elevated CE levels with a low FC/CE ratio. These results highlight that elevated FC levels with high FC/CE ratio are a risk factor for sepsis. Therefore, selectively targeting elevated FC levels and FC/CE ratio could be a promising therapeutic strategy for managing sepsis.

中文翻译：

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由于反向胆固醇转运受损导致游离胆固醇水平升高是小鼠多种微生物脓毒症的危险因素。


脂质代谢失调在脓毒症患者中很常见，但它如何导致脓毒症在很大程度上仍然未知。逆向胆固醇转运 （RCT） 对于调节循环中的胆固醇代谢至关重要。在 RCT 期间，高密度脂蛋白 （HDL） 从外周组织收集胆固醇并将其运输到肝脏的清道夫受体 BI （SR-BI），在那里 SR-BI 介导 HDL 中胆固醇酯的吸收，以便通过胆汁排泄。在这项研究中，我们利用 AlbCreSR-BIfl/fl 小鼠（一种 RCT 受损的模型）来研究 RCT 对脓毒症的影响。我们发现 AlbCreSR-BIfl/fl 小鼠对盲肠结扎和穿刺 （CLP） 诱导的多微生物败血症明显更敏感，存活率为 14.3%，而 SR-BIfl/fl 同窝小鼠为 80%。从机制上讲，败血症破坏了胆固醇代谢，导致 AlbCreSR-BIfl/fl 小鼠的游离胆固醇 （FC） 水平增加 4.8 倍，与 SR-BIfl/fl 同窝小鼠相比，FC/胆固醇酯 （CE） 比率增加 4 倍。这种破坏导致了溶血和死亡。值得注意的是，施用降胆固醇药物 probucol 使 FC 水平和 FC/CE 比率正常化，并显着提高了 CLP-AlbCreSR-BIfl/fl 小鼠的存活率。然而，probucol 治疗降低了 CLP-LDLR-/- 小鼠的存活率，该小鼠的 CE 水平升高，FC/CE 比率较低。这些结果强调，FC 水平升高和高 FC/CE 比率是脓毒症的危险因素。因此，选择性靶向升高的 FC 水平和 FC/CE 比率可能是管理脓毒症的一种有前途的治疗策略。